Medication-related osteonecrosis of the jaw (MRONJ) is a rare but serious drug-related
adverse event. To identify pharmacogenomic markers of MRONJ associated with bisphosphonate
therapy, we conducted a genomewide association study (GWAS) meta-analysis followed
by functional analysis of 5,008 individuals of European ancestry treated with bisphosphonates,
which includes the largest number of MRONJ cases to date (444 cases and 4,564 controls).
Discovery GWAS was performed in randomly selected 70% of the patients with cancer
and replication GWAS was performed in the remaining 30% of the patients with cancer
treated with intravenous bisphosphonates followed by meta-analysis of all 3,639 patients
with cancer. GWAS was also performed in 1,369 patients with osteoporosis treated with
oral bisphosphonates. The lead single-nucleotide polymorphism (SNP), rs2736308 on
chromosome 8, was associated with an increased risk of MRONJ with an odds ratio (OR)
of 2.71 and 95% confidence interval (CI) of 1.90?3.86 (P = 3.57*10?8) in the meta-analysis
of patients with cancer. This SNP was validated in the MRONJ GWAS in patients with
osteoporosis (OR: 2.82, 95% CI: 1.55?4.09, P = 6.84*10?4). The meta-analysis combining
patients with cancer and patients with osteoporosis yielded the same lead SNP rs2736308
on chromosome 8 as the top SNP (OR: 2.74, 95% CI: 2.09?3.39, P = 9.65*10?11). This
locus is associated with regulation of the BLK, CTSB, and FDFT1 genes, which had been
associated with bone mineral density. FDFT1 encodes a membrane-associated enzyme,
which is implicated in the bisphosphonate pathway. This study provides insights into
the potential mechanism of MRONJ.
